Background

No treatment has yet been shown to be effective in reducing morbidity and mortality in heart failure with preserved ejection fraction (HFpEF). Elevated heart rate is a predictive factor of worse outcomes in patients with HF, incuding in HFpEF.

Ivabradine is a selective inhibitor of the sino-atrial node If current, and thereby decreases heart rate. In animal models for HFpEF, ivabradine was shown to reduce cardiac fibrosis, improve vascular stiffness and cardiac function. The rationale for studying ivabradine in HFpEF is that the left ventricle is abnormally stiff, leading to an impaired left ventricular filling and an increase in pressures in the left atrium and upstream. Reducing the heart rate is expected to improve left ventricular filling and thereby cardiac function.

The EDIFY is a proof-of-concept study into whether heart rate reduction with ivabradine in HFpEF improves diastolic function, improves exercise capacity and reduces NT-proBNP/BNP levels. The three co-primary endpoints were E/e’-ratio, 6 minute walking distance (6MWD) and plasma NT-proBNP concentration. These endpoints were measured at the time of selection, which was about 2 weeks before the moment of inclusion, when the tests were repeated, as well as 2 months after inclusion, and 4 and 8 months after inclusion. Ivabradine treatment was started at 5 mg bid, and titrated to a target of 7.5 mg bid. Patients were 50 years or older and had symptomatic chronic HF with NYHA class II or III, which was stable for at least four weeks prior to selection. Of 654 screened and 422 selected patients, 243 were not included mostly due to having NT-proBNP<220 pg/mL, patients not being in sinus rhythm, having HR<70 bpm or unmet echocardiographic criteria. Recruitment was stopped before reaching the target of 400 patients.

Main results

Ivabradine resulted in a rapid decline of heart rate, which was sustained through the study period. Placebo showed a small decline and remained at this higher heart rate.

E/e’ ratio did not significantly change from baseline to end of study in patients treated with ivabradine (n=83) or placebo (n=83), nor did the groups differ significantly.

6MWT did not improve from baseline to end of study in either treatment group, and both groups showed similar distances.

NT-proBNP did not change significantly from baseline to the last measurement in either treatment group, nor did the treatment groups significantly differ.

Numerically more adverse events (AEs) were seen, including serious AEs, but this difference did not reach statistical significance.

Conclusion

These study data show that ivabradine does not benefit HFpEF patients. This might be the consequence of the fact that the population enrolled had rather advanced HFpEF with extensive myocardial fibrosis. Another explanation may lie in the lack of sufficient power due to screening failures, although no significant improvements were seen in the co-secondary endpoints. Moreover, it is possible that a particular phenotype was selected (sinus rhythm), which does not reflect the various subcategories of HFpEF patients.

Thus, it was concluded that in the EDIFY study population, HR reduction with ivabradine did not show a beneficial effect on cardiac filling pressure (E/e’), exercise capacity (6MWD) and plasma NT-proBNP concentrations over 8 months. Hence, these findings do not support the use of ivabradine in this type of patients with HFpEF. Further studies may explore whether other HFpEF phenotypes may benefit from HR reduction. In these data, no subgroups were identified that benefitted from ivabradine.

Discussant Gerasimos Filippatos (Athens, Greece) noted that indeed HFpEF is difficult to treat because it is such a heterogeneous population. Also, he said that it is difficult to see an improvement in NT-proBNP if the mean was between 300 and 400 pf/mL, and 6MWD was around 320 meters, which is quite good for patients aged 72-73 on average.

Furthermore, he questioned whether we know that the HR target is the same in HFpEF as in HFrEF, and whether 8 months is enough to see an effect of reverse modelling. Again, the conclusion is that a lot remains unknown about HFpEF.

Disclosures

Our coverage of ESC HF 2017 is based on the information provided during the congress.